Tilidine dihydrogen orthophosphate, method of preparing it and pharmaceutical preparation containing it

ABSTRACT

The instant invention is a tilidine salt, tilidine dihydrogen orthophosphate, which owing to its surprising stability, is particularly suitable for use in the preparation of solid, in particular delayed-action, drugs in tablet, pill or capsule form.

This is a 371 of PCT/EP93/02954 filed Oct. 25, 1993.

BACKGROUND OF THE INVENTION

The instant invention is for the new salt, tilidine dihydrogenorthophosphate, a process for its preparation and pharmaceuticalcompositions containing it. Tilidine (±)-ethyltrans-2-dimethylamino-1-phenyl-3-cyclohexene-trans-1-carboxylate)! is acommercially available analgesic which is enterally resorbed veryquickly and is especially suitable for the treatment of very severepains. For galenical compositions, salts of the basic active materialare used since the base as such does not have sufficient stability overa comparatively long period of time. Until now for reasons of stability,even with the use of salts, it has not been possible to develop solidpharmaceutical forms, such as tablets or suppositories.

Only the hydrochloride semihydrate (DE-PS 1 518 959 and 1 793 571 U.S.Pat. No. 3,557,127!) has, in practice, proved to be useful as a salt forstable liquid compositions. It is commercially available in the form ofa solution or of a portioned suspension in soft gelatin capsules underthe trademark Valoron N. Because of its outstanding properties incombatting pain, Valoron N has become one of the leading analgesics inGermany. All endeavors to make available useful solid pharmaceuticalforms of the active material tilidine have been unsuccessful because ofthe stability problems. There is a need for a useable solid galenicalform of tilidine because only such a solid formulation can provide acontrollable release of tilidine. Tilidine acts for a relatively shortperiod of time and a uniform treatment of pain for a comparatively longperiod of time, with a single dose of active material is needed. Normalrelease, such as is provided by liquid compositions, is problematical. Asustained form would be a very great advance in the field of analgesicsand especially where a uniform, high level of active material over along period of time is required. Such a form would be useful incombatting chronic and severe painful conditions such as in thetreatment of cancer and in the treatment of burns.

SUMMARY OF THE INVENTION

The present invention provides a tilidine salt which is stable in solidand sustained pharmaceutical compositions, especially in tablets, coatedtablets, and suppositories. A process for the production of solid andsustained pharmaceutical compositions of this new salt is included.

The new salt is tilidine dihydrogen orthophosphate.

The invention covers a solid, sustained-release pharmaceuticalcomposition comprising:

(a) tilidine dihydrogen orthophosphate, and

(b) conventional solid pharmaceutical adjuvants.

The pharmaceutical composition can also contain one or more agents forsustained release.

The composition is selected from: a tablet, a coated tablet, a capsule,a suppository, or a granulate.

Further, the invention involves a process for the preparations oftilidine dihydrogen orthophosphate comprising:

(a) dissolving tilidine base in isopropanol containing 4-10% by weightwater, and warming to from 30°-50° C.,

(b) stirring while adding a solution of 80-90% orthophosphoric acid overa period of about 3 hours while adding seed crystals continuously,

(c) cooling slowly to room temperature while stirring, and

(d) centrifuging and washing the product from (c) above.

A more preferred process for producing tilidine dihydrogen phosphatecomprises:

(a) dissolving tilidine base in isopropanol containing 4-10% by weightwater, and warming to 35°-45° C.,

(b) stirring while adding a solution of 85-88% orthophosphoric acid overa period of 3 hours while adding seed crystals continuously,

(c) cooling the product of step (b) above overnight to room temperaturewith stirring, and

(d) centrifuging the crystals from step (c) above and washing twice with10 L of 94% isopropanol.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the IR spectrum of the salt of the invention.

DETAILED DESCRIPTION

Surprisingly, we have now found that tilidine dihydrogen orthophosphatehas outstanding stability and is the only salt suitable for theproduction of solid pharmaceutical compositions. In solid form, incombination with solid adjuvants, it undergoes practically nodecomposition. Further, the new salt has surprisingpharmaceutical-technological properties which are superior to theproperties of other tilidine salts, such as, tilidine hydrogen sulfateor tilidine hydrogen fumarate. It can be prepared without specialrequirements as to the climate in the production rooms and the corrosionprotection of the apparatus and tools used. Granulates, tablets, andsuppositories can be produced which are storage stable not onlychemically but also physically over a very long period of time.

In DE-1 923 619, (U.S. Pat. No. 3,649,628) it is mentioned in passingthat basically substituted cyclohexenes can form salts with a number oforganic and inorganic acids, inter alia also with phosphoric acid whichcan possibly be considered for working up to give pharmaceuticalcompositions. No phosphate is described and especially not tilidinedihydrogen orthophosphate. Moreover, the above-mentioned stabilityproblems and especially those of tilidine are not described. Hitherto,there has been no indication in the literature regarding thedifficulties concerning the storage stability of this active material orof the technical problems when it is worked up to give solidpharmaceutical compositions. Therefore, one had no reason or noindication that precisely tilidine dihydrogen orthophosphate would beespecially suitable for solving the above problems.

In addition, it has been found that the methods used in the productionof the phosphate is critical and must to be carried out under veryspecial conditions if a crystalline product of high purity is to beobtained. The salt formation is started with 80-90%, preferred 85-88%orthophosphoric acid, which is dissolved in an amount of watercontaining isopropanol (water content 4-10% by weight, preferred 6%)which is suitable for a complete solution. This solution is combined ata temperature of 30°-50° C., preferred 40°±5° C. with a solution of0.8-1.2 mol, preferred 1 mol of tilidine base in isopropanol of theabove given water content under stirring in about stoichiometric amountsand the suspension obtained is slowly (over several hours) cooled understirring. After washing with the isopropanol tilidine dihydrogenorthophosphate of 99.5% purity in a yield of more than 90% is obtained.Both the water content and reaction temperature parameters areimportant. At temperatures below 35° C. and with water products withimpurities of the solvents and bad crystallization behavior, productswhich are not completely dryable and which retain persistent isopropanolare produced.

Therefore, the present invention provides tilidine dihydrogenorthophosphate and a process for the preparation thereof. The presentinvention also provides a solid and especially a sustained-release solidgalenical pharmaceutical composition consisting of conventional solidpharmaceutical adjuvants, as well as, if desired, releasing agents,which is characterized by tilidine dihydrogen orthophosphate as theactive material, and the production thereof.

For the production of sustained-release solid pharmaceuticalcompositions containing tilidine, all conventional processes forsustained-release which do not have a negative influence on thestability of the active material on the basis of their composition. Asustained-release tablet prepared by a melt process according to EP-PS 0043 254 (U.S. Pat. No. 4,483,847) is especially useful. Generally, assustained-release agents any sparingly soluble material can be used, forexample lipid or lipoid substance such as stearic acid and especiallyhydrogenated castor oil (Cutina HR) (DE-A 1 617 657 3,487,138) and U.S.Pat. No. 4,123,753) or hydrophilic polymers, which, as swellingmaterials, delay the liberation of the active material (see J. Pharm.Sci., p. 974/1966). For the objective control of the rate of liberationthe process according to EP-PS 0 068 446 (U.S. Pat. No. 4,608,248) canalso be used through the rate of liberation of the active material froman active material composition made sustained by means ofsparingly-soluble substance is adjusted by the viscosity of an addedhydrophilic polymer, for example methyl cellulose or carboxymethylcellulose, since the speed of liberation increases with increasingviscosity.

The surprising superiority of the dihydrogen orthophosphate isdemonstrated by comparison with:

(a) tilidine hydrochloride semihydrate

(b) tilidine hydrogen fumarate

(c) tilidine hydrogen sulphate and

(d) tilidine dihydrogen orthophosphate.

In each case the compound was triturated with naloxone hydrochloridedihydrate and conventional adjuvants. Naloxone hydrochloride semihydrateis an effective morphine antagonist which commercially availabletilidine compositions contain. After storage for 28 days at 60° C.,distinct differences are shown in the four salts: whereas mixtures a) toc) were substantially discolored, mixtures of d) showed no change ofcolor and thus, no decomposition phenomena.

In a further experiment, three different salts of tilidine were, in eachcase, worked up with naloxone hydrochloride dihydrate, hydrogenatedcastor oil, lactose, hydroxyethyl cellulose, stearic acid, tablettoseand magnesium stearate to give melt granulate tablets. With tilidinehydrogen fumarate, event in the case of the production of the meltgranulate, there was shown a strong green coloration. The tablets withtilidine hydrochloride semihydrate showed orange-grey discolorationsafter only two days storage in brown glass containers at 22° C. On theother hand, the tablets with tilidine dihydrogen orthophosphate showedno discolorations under the same conditions even after storage for sixmonths.

In the product samples, the new dihydrogen orthophosphate also proved tobe extremely good with regard to the working up properties.

It was not hygroscopic, did not react with metallic materials and wasinert towards electrostatic charging. At a relative humidity of 63%, thehydrochloride semihydrate took up considerable amounts of water andacted corrosively on tools which were not specially protected againstcorrosion. In the case of a relative atmospheric humidity of 58%, thesulphuric acid salt already took up water and exceeded the hydrochloridesemihydrate in its aggressive corrosion behavior. The would causeimprecise weighed amounts and the partial demixing of the adjuvant andactive materials.

The following examples are for the purpose of illustrating the presentinvention; they are not intended to limit its scope in any way.

EXAMPLE 1

Preparation of tilidine dihydrogen orthophosphate: 27.091 kg (99.10 mol)tilidine base were dissolved in 99 L of 94% isopropanol (6% water) withwarming to about 40° C. (±5° C.). While stirring, a solution of 11.54 kgof 85-88% orthophosphoric acid (corresponding to 9.844 kg=100.46 mol of100%, acid) was added thereto at 40° C. over 3 hours. For improvedcrystallization, seed crystals were continuously added. The suspensionwas slowly cooled overnight to ambient temperature, while stirring. Thecrystals were centrifuged off and washed twice with 10 L of 94%isopropanol. The white salt obtained was dried at 50 to 60° C. Yield:33.89 kg (92.09% of theory). The salt had an analytical purity (HPLC) of99.5%, mp 137.0° C. Molecular weight: 371.37. For IR spectrum of thesalt see in FIG. 1.

EXAMPLE 2

Retarded (sustained release) tablets containing 120 mg of tilidinedihydrogen orthophosphate: 960 g tilidine dihydrogen orthophosphate,prepared according to Example 1, were premixed with 70.4 g naloxonehydrochloride dihydrate, 740 g lactose and 700 g hydrogenated castor oiland then slowly heated with continuing mixing to a product temperatureof 83° C. The resultant melt mass was removed from the mixing vessel andpassed through a sieve of 2.5-mm size. After cooling to ambienttemperature, the product was passed through a further sieve of 1-mm meshsize. Subsequently, 273.6 g ammonia methacrylate copolymer, 32 gmagnesium stearate and 24 g silicon dioxide were sieved and uniformlymixed with granulate. The mixture was then pressed with an eccentricpress to provide round, slightly domed tablets of 10-mm diameter, 11-mmdome radius and 350-mg nominal weight. The tablets have the followingcomposition:

    ______________________________________                                        tilidine dihydrogen orthophosphate                                                                     120.0  mg                                            naloxone hydrochloride dihydrate USP                                                                   8.8    mg                                            lactose                  92.5   mg                                            hydrogenated castor oil  87.5   mg                                            ammonia methacrylate copolymer                                                                         34.2   mg                                            magnesium stearate       4.0    mg                                            silicon dioxide          3.0    mg                                            ______________________________________                                    

The following product properties were determined for the tabletsobtained:

weight average value: 351 mg, minimum 340 mg, maximum 363 mg, S_(rel)1.8%

breaking strength: average value 82N, minimum 64N, maximum 90N, S_(rel)8.4%

friability: 0.23%

breakdown: more than 3 hours.

EXAMPLE 3

Suppositories containing 59.95 mg tilidine dihydrogen orthophosphate:9700 g hard fat with a hydroxyl number 40-50 (Witepsol W 35 R!) or analternative hard fat with a hydroxyl number of up to 2 (massa estarinumR 299) was melted at 45° C. in a heatable vessel equipped with a stirreruntil completely clear. After cooling to 36° to 38° C., 300 g tilidinedihydrogen orthophosphate were dispersed in the molten fat base with thehelp of an Ultra-Turrax (R) mixer. The product temperature was therebymaintained at 36° to 38° C., possibly with cooling of the mantle of thevessel. The melt ready for casting was then poured out in a shaping,filling and closing machine into suppository blisters made oftriple-laminate film. The casting temperature at the dosing plant wasmaintained at 37° C. During the casting, the temperature of the vesselwas 37° C. The dosage amount per filling station was 2.0 g±5%. Thesuppositories were cooled during transport through a cooling tunnel inwhich a temperature of 20 to ° C. prevailed and thereby solidified. Theblisters were subsequently heat-sealed and stamped out. In this way, upto 9000 suppositories were produced per hour. The batch used in thepresent example provided 4850 suppositories each containing 59.93 mgtilidine dihydrogen orthophosphate (corresponding to 50 mg tilidinehydrochloride).

We claim:
 1. The compound tilidine dihydrogen orthophosphate.
 2. Asolid, sustained-release pharmaceutical composition comprising:(a)tilidine dihydrogen orthophosphate, and (b) conventional solidpharmaceutical adjuvants.
 3. A composition according to claim 2containing one or more sustained-release agents.
 4. The compositionaccording to claim 2, selected from a tablet, a coated tablet, acapsule, a suppository, or a granulate.
 5. A process for thepreparations of tilidine dihydrogen orthophosphate comprising:(a)dissolving tilidine base in isopropanol containing 4-10% by weight,water, and warming to from 30°-50° C., (b) stirring while adding asolution of 80-90% orthophosphoric acid over a period of about 3 hourswhile adding seed crystals continuously, (c) cooling slowly to roomtemperature while stirring, and (d) centrifuging and wash the productfrom (c) above.
 6. A process according to claim 5 comprising:(a)dissolving tilidine base in isopropanol containing 4-10% by weight waterand warming to 35°-45° C., (b) stirring while adding a solution of85-88% orthophosphoric acid over a period of 3 hours while adding seedcrystals continuously, (c) cooling the product of step (b) aboveovernight to room temperature with stirring, and (d) centrifuging thecrystals from step (a) above and washing twice with 10 L of 94%isopropanol.